Hypoxia inducible factor-1 (HIF-1) is a heterodimeric transcriptional activator that regulates the expression of genes involved in adaptation to hypoxic stress. HIF-1 is composed of two subunits referred to as HIF-1α and HIF-1β. These subunits are expressly constitutively. During normal conditions, HIF-1α is targeted to ubiquitination and proteosomal degradation following hydroxylation of HIF-1 at proline 402 and 564 by the enzyme, prolyl hydroxylase.
Prolyl hydroxylases are reported to be oxygen-dependent. For example, under conditions of reduced oxygen, these enzymes function with low efficiency. As a result, HIF-1α is not hydroxylated, and thus not targeted to ubiquitination and degradation. Accordingly, HIF-1α becomes stabilized, and can bind HIF-1β to activate genes involved in adaptation to oxidative stress.
Oxidative stress is reported to be associated with numerous diseases and conditions, including stroke, hypoxia, ischemia, spinal cord injury and neurodegenerative conditions. Thus, compounds which enhance the activity of HIF-1α protein are beneficial for treating conditions and diseases associated with oxidative stress.